Return of Chloroquine‐Susceptible Falciparum Malaria in Malawi Was a Reexpansion of Diverse Susceptible Parasites

Abstract

The spread of drug-resistant Plasmodium falciparum malaria has been a major impediment to malaria control and threatens prospects for elimination. We recently demonstrated the return of chloroquine-susceptible malaria in Malawi after chloroquine use was abandoned. In this study, we trace the origins of chloroquine-resistant and chloroquine-susceptible parasites in Malawi by sequencing the P. falciparum chloroquine resistance transporter gene (pfcrt) and by genotyping microsatellites flanking this gene in isolates from infections that occurred in Malawi from 1992 through 2005. Malaria parasites from 2005 harbored the expected wild-type pfcrt haplotype associated with chloroquine susceptibility and have maintained high levels of diversity without linkage disequilibrium, which suggests that the return of chloroquine susceptibility is not the result of a back mutation in a formerly resistant parasite or a new selective sweep. Chloroquine-susceptible parasites that predominate in Malawi likely represent a reexpansion of the susceptible parasites that survived in the population despite widespread drug pressure in the region.

Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

“…S2). Additionally, the absence of a significant chloroquine sensitivity signal at pfcrt is consistent with reports that the return of chloroquine-sensitive parasites in Africa did not result from a classic selective sweep (26). In either case, the Manhattan-like z-score plots allow us to note the presence of these drug-sensitivity signals while keeping them visually separate from the drug resistance signals on which we wish to focus.…”

Discordant Temporal Evolution of Pfcrt and Pfmdr1 Genotypes and Plasmodium falciparum In Vitro Drug Susceptibility to 4-Aminoquinolines after Drug Policy Change in French Guiana

“…In Malawi, withdrawal of chloroquine was followed by the expansion of chloroquine-sensitive parasites possessing a wild-type Pfcrt allele, apparently better fit than mutant parasites in the absence of chloroquine pressure (26,32). A similar phenomenon was reported in China (44).…”

Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt

“…This situation contrasts with multiple settings in Africa, where the majority of molecular studies (10)(11)(12)(13) have documented an increase in the prevalence of WT pfcrt after CQ withdrawal. An analysis of the diversity of microsatellites flanking pfcrt in Malawi showed that the return to CQ susceptibility was caused by a reexpansion of the WT PfCRT haplotype (11). Such a difference between South America and other endemic regions in response to CQ withdrawal is generally attributed to other amino acid changes in PfCRT and PfMDR1 (both present on the parasite digestive vacuole membrane), which accompany the PfCRT K76T substitution.…”

“…In South America, the prevalence of the CQR marker K76T in the drug efflux transmembrane protein PfCRT has remained high, despite CQ having been abandoned for the treatment of P. falciparum infections (7)(8)(9). This situation contrasts with multiple settings in Africa, where the majority of molecular studies (10)(11)(12)(13) have documented an increase in the prevalence of WT pfcrt after CQ withdrawal. An analysis of the diversity of microsatellites flanking pfcrt in Malawi showed that the return to CQ susceptibility was caused by a reexpansion of the WT PfCRT haplotype (11).…”